Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice

Concanavalin A (Con A) causes severe TNF-alpha -mediated and IFN-gamma -med iated liver injury in mice. In addition to their other functions, TNF-alpha and IFN-gamma both induce the inducible nitric oxide (NO) synthase (iNOS). Using different models of liver injury, NO was found to either mediate or prevent liver damage. To further elucidate the relevance of NO for liver da mage we investigated the role of iNOS-derived NO in the Con A model. We rep ort that iNOS mRNA was induced in livers of Con A-treated mice within 2 hou rs, with iNOS protein becoming detectable in hepatocytes as well as in Kupf fer cells within 4 hours. iNOS(-/-) mice were protected from liver damage a fter Con A treatment, as well as in another TNF-alpha -mediated model that is inducible by LPS in D-galactosamine-sensitized (GalN-sensitized) mice. i NOS-deficient mice were not protected after direct administration of recomb inant TNF-alpha to GalN-treated mice. Accordingly, pretreatment of wild-typ e mice with a potent and specific inhibitor of iNOS significantly reduced t ransaminase release after Con A or GalN/LPS, but not after GalN/TNF-alpha t reatment Furthermore, the amount of plasma TNF-alpha and of intrahepatic TN F-alpha mRNA and protein was significantly reduced in iNOS(-/-) mice. Our r esults demonstrate that iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver injury in mice by stimulat ion of TNF-alpha production.